Project Summary Rescue/recovery work at the World Trade Center (WTC) disaster site caused a decline in lung function in Fire Department of the City of New York (FDNY) firefighters. Over 15 years of post-exposure follow-up, 1 in 8 WTC- exposed firefighters experienced accelerated FEV1 decline, a FEV1 loss >64 ml/year. Accelerated FEV1 decline is associated with chronic obstructive pulmonary disease (COPD) and asthma. Despite the high burden of respiratory diseases there are no evidence-based indications for inhaled corticosteroid (ICS) combined with long-acting beta-agonist (LABA) treatment in patients whose only defining characteristic is accelerated FEV1 decline. Only 35% of WTC-exposed FDNY firefighters with accelerated FEV1 decline have been treated with ICS/LABA. If the rapid rate of FEV1 loss in the accelerated FEV1 decline population is not reduced, patients with accelerated FEV1 decline will likely develop COPD, the fourth leading cause of death in the United States. Determining if ICS/LABA treatment is effective in blunting FEV1 decline in these patients would have important implications not only for WTC-exposed cohorts, but also for other workplace respiratory disease surveillance. In preliminary analyses, we found that ICS/ LABA use is associated with worse lung function and reduced quality of life. This observation is consistent with selection by indication bias, whereby sicker individuals are the ones who are treated. To mitigate the effects of this bias, we used treated patients as their own controls, examining FEV1 trajectory prior to and after initiation of ICS/LABA therapy. After ICS/LABA initiation, FEV1 trajectory improved by 9.91.1 ml/year (meanSEM). This grant will explore heterogeneity in ICS/LABA response. The current multi-center collaboration aims to estimate how many in the untreated accelerated decline group have a pretreatment phenotype predictive of significant ICS/LABA benefit. This proposal tests the overall hypothesis that ICS/LABA treatment improves FEV1 trajectory in accelerated FEV1 decline patients, and that specific patient characteristics, including elevated blood eosinophils, will be associated with a favorable response to ICS/LABA treatment. Specific Aim 1 will use ICS/LABA-treated patients as their own controls, assessing FEV1 trajectory before and after ICS/LABA initiation, and testing whether inflammatory biomarkers (notably, blood eosinophils), pulmonary physiology and demographic factors are predictors of response to therapy. Specific Aim 2 will adjust for selection by indication bias to identify untreated individuals most likely to respond to treatment, using data from the full cohort of treated and untreated WTC-exposed rescue and recovery workers. These data will enable the development of models that predict ICS/LABA treatment response in untreated individuals. When modeling the effect of ICS/LABA on the FEV1 trajectory of the untreated workers with accelerated FEV1 decline, we will identify those with high probability of benefiting from ICS/LABA medications, a central goal of the NIOSH WTC Health Program's ?Research to Care? translational model. ! !